Pharmacokinetics and Safety of Prolonged Paracetamol Treatment in Neonates: An Interventional Cohort Study

Aims To investigate the pharmacokinetics and safety of prolonged paracetamol use (\u3e72 h) for neonatal pain. Methods Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. Results Forty-eight neonates were enrolled (38 received paracetamol for \u3e72 h). Median gestational age was 38 weeks (range 25–42), and bodyweight at inclusion was 2954 g (range 713–4750). Neonates received 16 doses (range 4–55) over 4.1 days (range 1–13.8). The median (range) dose was 10.1 mg/kg (2.9–20.3). The median oxidative metabolite concentration was 14.6 μmol/L (range 0.12–113.5) and measurable \u3e30 h after dose. There was no significant difference (P \u3e .05) between alanine aminotransferase and bilirubin measures at \u3c72 h or \u3e72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44–3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425–0.570), respectively. Median steady-state concentration from the parent model was 50.3 μmol/L (range 30.6–92.5), and the half-life was 3.55 h (range 2.41–5.65). Conclusion Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates

Correlation between relative rates of hospital treatment or death due to ischaemic heart disease (IHD) and of IHD-related medication among socio-occupational and economic activities groups in Denmark, 1996–2005

Objective: The aim of the present work was to establish whether or not prescribed medication is a usable risk indicator for work‑related ischaemic heart disease (IHD), in Denmark. Material and Methods: Weighted Spearman rank correlation coefficients (rho) were used to evaluate the agreement between Standardised Hazard Ratios (SHR) for hospital treatment or death due to IHD and SHR for purchase of prescriptions for medicine that may prevent IHD from (re)occurring, among socio-occupational and economic activities groups in Denmark. The SHR were based on a 10-year prospective follow-up of 2 million people in Danish national registers 1996–2005. Results: We found approximately 7 times more cases of medicine usage (N = 411 651) than we did for hospital treatment or death (N = 55 684). The correlations between the 2 types of SHR were strong (rho = 0.94 for the socio-occupational groups; rho = 0.74 for the economic activities groups). We observed, however, one markedly contradictive result; the industrial group entitled ‘general practitioner, dentists etc.’ was associated both with significantly high rates of medicine usage (SHR = 1.15, 95% CI: 1.12–1.19) and significantly low rates of hospital treatment or death due to IHD (SHR = 0.80, 95% CI: 0.71–0.91). Conclusion: Apart from a few caveats, the strong correlations obtained in the present study signify that purchase of a prescription for IHD-related medication is a usable risk indicator for IHD in the working population of Denmark. The usage of medicine data in addition to or instead of the use of death or hospital data in epidemiological studies on work-related IHD risk will bring about a tremendous increase in statistical power